F. M. Singer et al., Proc. Soc. Exper. Biol. Med., 102, 370 (1959) and F. H. Hulcher, Arch. Biochem. Biophys., 146, 422 (1971) disclose that certain mevalonate derivatives inhibit the biosynthesis of cholesterol.
Endo et al in U.S. Pat. Nos. 4,049,495, 4,137,322 and 3,983,140 disclose a fermentation product which is active in the inhibition of cholesterol biosynthesis. This product is called compactin and was reported by Brown et al., (J. Chem. Soc. Perkin I. 1165 (1976) to have a complex mevalonolactone structure.
GB 1,586,152 discloses a group of synthetic compounds of the formula ##STR3## in which E represents a direct bond, C.sub.1-3 alkylene bridge or a vinylene bridge and the various R's represent a variety of substituents.
The activity reported in the U.K. patent is less than 1% that of compactin.
U.S. Pat. No. 4,375,475 to Willard et al discloses hypocholesterolemic and hypolipemic compounds having the structure ##STR4## wherein A is H or methyl; E is a direct bond, --CH.sub.2 --, --CH.sub.2 --CH.sub.2 --, --CH.sub.2 --CH.sub.2 --CH.sub.2 -- or --CH.dbd.CH--; R.sub.1, R.sub.2 and R.sub.3 are each selected from H, halogen, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, phenyl, phenyl substituted by halogen, C.sub.1-4 alkoxy, C.sub.2-8 alkanoyloxy, C.sub.1-4 alkyl, or C.sub.1-4 haloalkyl, and OR.sub.4 in which R.sub.4 is H, C.sub.2-8 alkanoyl, benzoyl, phenyl, halophenyl, phenyl C.sub.1-3 alkyl, C.sub.1-9 alkyl, cinnamyl, C.sub.1-4 haloalkyl, allyl, cycloalkyl-C.sub.1-3 -alkyl, adamantyl-C.sub.1-3 -alkyl, or substituted phenyl C.sub.1-3 -alkyl in each of which the substituents are selected from halogen, C.sub.1-4 alkoxy, C.sub.1-4 alkyl, or C.sub.1-4 haloalkyl; and the corresponding dihydroxy acids resulting from the hydrolytic opening of the lactone ring, and the pharmaceutically acceptable salts of said acids, and the C.sub.1-3 alkyl and phenyl, dimethylamino or acetylamino substituted C.sub.1-3 -alkyl esters of the dihydroxy acids; all of the compounds being the enantiomers having a 4 R configuration in the tetrahydropyran moiety of the trans racemate shown in the above formula.
WO 84/02131 (PCT/EP83/00308) (based on U.S. application Ser. No. 443,668, filed Nov. 22, 1982, and U.S. application Ser. No. 548,850, filed Nov. 4, 1983), filed in the name of Sandoz AG discloses heterocyclic analogs of mevalono lactone and derivatives thereof having the structure ##STR5## wherein one of R and R.sub.o is ##STR6## and the other is primary or secondary C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl or phenyl--(CH.sub.2).sub.m --,
wherein R.sub.4 is hydrogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, (except t-butoxy), trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy, PA1 R.sub.5 is hydrogen, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy, PA1 R.sub.5a is hydrogen, C.sub.1-2 alkyl, C.sub.1-2 alkoxy, fluoro or chloro, and PA1 m is 1, 2 or 3, PA1 with the provisos that both R.sub.5 and R.sub.5a must be hydrogen when R.sub.4 is hydrogen, R.sub.5a must be hydrogen when R.sub.5 is hydrogen, not more than one of R.sub.4 and R.sub.5 trifluoromethyl, not more than one of R.sub.4 and R.sub.5 is phenoxy and not more than one of R.sub.4 and R.sub.5 is benzyloxy, PA1 R.sub.2 is hydrogen, C.sub.1-4 alkyl, C.sub.3-6 cycloalkyl, C.sub.1-4 alkoxy (except t-butoxy), trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy, PA1 R.sub.3 is hydrogen, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy, with the provisos that R.sub.3 must be hydrogen when R.sub.2 is hydrogen, not more than one of R.sub.2 and R.sub.3 trifluoromethyl, not more than one of R.sub.2 and R.sub.3 is phenoxy, and not more than one of R.sub.2 and R.sub.3 is benzyloxy. PA1 Z is ##STR7## wherein R.sub.6 is hydrogen or C.sub.1-3 alkyl in free acid form or in the form of a physiologically-hydrolysable and -acceptable ester or a .delta. lactone thereof or in salt form. PA1 Pr=a carbinol-protecting group; PA1 R.sup.1 =H or CH.sub.3 ; PA1 R.sup.3, R.sup.4 =H, 1-3C alkyl or phenyl-(1-3C alkyl), the phenyl being optionally substituted by 1-3C alkyl, 1-3C alkoxy or halo; PA1 R.sup.2 =a group of formula (A) or (B): ##STR11## Q= ##STR12## R.sup.6 =H or OH; R=H or CH.sub.3 ; PA1 a, b, c and d=optional double bonds; PA1 R.sup.7 =phenyl or benzyloxy, the ring in each case being optionally substituted by 1-3C alkyl or halo; PA1 R.sup.8, R.sup.9 =1-3C alkyl or halo; PA1 R.sup.5 =1-3C alkyl, phenyl or mono- or di-(1-3C alkyl)phenyl. PA1 R.sub.3 is hydrogen, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy, with the provisos that not more than one of R.sub.2 and R.sub.3 is trifluoromethyl, not more than one of R.sub.2 and R.sub.3 is phenoxy, and not more than one of R.sub.2 and R.sub.3 is benzyloxy, PA1 R.sub.1 is hydrogen, C.sub.1-6 alkyl, fluoro, chloro or benzyloxy, PA1 R.sub.4 is hydrogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, (except t-butoxy), trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy, PA1 R.sub.5 is hydrogen, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy, PA1 R.sub.5a is hydrogen, C.sub.1-2 alkyl, C.sub.1-2 alkoxy, fluoro or chloro, and with the provisos that not more than one of R.sub.4 and R.sub.5 is trifluoromethyl, not more than one of R.sub.4 and R.sub.5 is phenoxy and not more than one of R.sub.4 and R.sub.5 is benzyloxy, PA1 X is ##STR16## wherein n is 0, 1, 2 or 3 and both q's are 0 or one is 0 and the other is 1, PA1 Z is ##STR17## wherein R.sub.6 is hydrogen or C.sub.1-3 alkyl, with the general proviso that --X--Z and the R.sub.4 bearing phenyl group are ortho to each other; PA1 in free acid form or in the form of a physiologically-hydrolysable and acceptable ester or a .delta. lactone thereof or in salt form. PA1 R.sub.1, R.sub.2 and R.sub.3 are, e.g., hydrogen, chloro, bromo, fluoro, C.sub.1 -alkyl, phenyl, substituted phenyl or OR.sub.7 in which R.sub.7 is, e.g., hydrogen, PA1 C.sub.2-8 alkanoyl, benzoyl, phenyl, substituted phenyl, C.sub.1-9 alkyl, cinnamyl, C.sub.1-4 haloalkyl, allyl, cycloalkyl-C.sub.1-3 alkyl, adamantyl-C.sub.1-3 -alkyl, or phenyl C.sub.1-3 alkyl; PA1 R.sup.4, R.sup.5 and R.sup.6 are hydrogen, chloro, bromo, fluoro or C.sub.1-3 alkyl; and PA1 X is, e.g., hydrogen, C.sub.1-3 alkyl, a cation derived from an alkali metal or is ammonium. PA1 R.sub.3 and R.sub.4 =H, lower alkyl or optionally substituted aryl or aralkyl. PA1 E is --CH.sub.2 CH.sub.2, --CH.dbd.CH--, or --(CH.sub.2).sub.r --; and PA1 Z is ##STR22## wherein X is --O--or --NR.sup.9 wherein R.sup.9 is hydrogen or C.sub.1-3 alkyl; PA1 R.sup.7 is C.sub.2-8 alkyl; and PA1 R.sup.8 is hydrogen or CH.sub.3 ; ##STR23## wherein R.sup.10, R.sup.11 and R.sup.12 are independently, e.g., hydrogen, halogen or C.sub.1-4 alkyl; ##STR24## PA1 X is --O-- or --NH--; PA1 n is 1 or 2; PA1 Z is a hydrophobic anchor; PA1 and including pharmaceutically acceptable salts thereof. PA1 R.sup.6 is lower ##STR30## R.sup.6a is lower alkyl, hydroxy, oxo or halogen; q is 0, 1, 2 or 3, and R.sup.7 is H or lower alkyl; PA1 X is O or NH; and PA1 Z is ##STR33## wherein R.sup.1 is phenyl which includes an alkyl and/or halo substitutent or R.sup.1 is benzyloxy which includes a halo substituent; PA1 R.sup.2 and R.sup.2a are the same and are halogen or lower alkyl; PA1 Z may also preferably be ##STR34## wherein R.sup.1 and R.sup.2 are as defined immediately above with respect to the compound of formula II, or PA1 Z is ##STR35## wherein R.sup.5 is H, CH.sub.3 or OH and R.sup.6 is ##STR36## or (substituted)phenylmethyl wherein R.sup.7 is H or CH.sub.3. PA1 where R.sup.b is lower alkyl)
X is --(CH.sub.2).sub.n -- or --CH.dbd.CH-- (n=0, 1, 2 or 3),
GB 2162-179-A discloses naphthyl analogues of mevalolactone useful as cholesterol biosynthesis inhibitors having the structure ##STR8## wherein R.sub.1 =1-3C alkyl; Z is a gp. of formula Z.sub.1 or Z.sub.2 : ##STR9## R.sub.7 =H, a hydrolysable ester gp. or a cation.
European Pat. No. 164-698-A discloses preparation of lactones useful as anti-hypercholesterolemic agents by treating an amide with an organic sulphonyl halide R.sup.5 SO.sub.2 X, then removing the protecting group Pr. ##STR10## wherein X=halo;
Anderson, Paul Leroy, Ger. Offen. DE3,525,256 discloses naphthyl analogs of mevalonolactones of the structure ##STR13## wherein R.sup.1 is alkyl, Z=Q, Q.sup.1 ; R.sup.7 =H, or a hydrolyzable ester group useful as inhibitors of cholesterol biosynthesis and in treatment of atherosclerosis.
WO 8402-903 (based on U.S. application Ser. No. 460,600, filed Jan. 24, 1983) filed in the name of Sandoz AG discloses mevalono-lactone analogues useful as hypolipoproteinaemic agents having the structure ##STR14## wherein the two groups Ro together form a radical of formula ##STR15## wherein R.sub.2 is hydrogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, (except t-butoxy), trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy,
European patent application No. 127,848-A (Merck & Co, Inc.) discloses derivatives of 3-hydroxy-5-thia-.omega.-aryl-alkanoic acids having the structural formula: ##STR18## wherein Z is: ##STR19## n is 0, 1 or 2; E is --CH.sub.2 --, --CH.sub.2 --CH.sub.2 --, --CH.sub.2 --CH.sub.2 --CH.sub.2 --, --CH.dbd.CH--CH.sub.2 --; or --CH.sub.2 --CH.dbd.CH--;
Those compounds have antihypercholesterolemic activity by virtue of their ability to inhibit 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase and antifungal activity.
French patent application No. 2,596,393 A filed on Apr. 1, 1986 (Sanofi SA) discloses 3-carboxy-2-hydroxy-propane-phosphonic acid derivatives including salts thereof which are useful as hypolipaemic agents and have the formula: ##STR20## wherein R.sub.1 and R.sub.2 =H, lower alkyl or optionally substituted aralkyl;
These compounds are disclosed as giving greater reductions in cholesterol, triglyceride and phospholipid levels than meglutol.
European patent application No. 142,146-A (Merck & Co., Inc) discloses mevinolin-like compounds of the structural formula: ##STR21## wherein: R.sup.1 is, e.g., hydrogen or C.sub.1-4 alkyl;